A myxovirus designated influenza is the etiological agent of the common "flu", an acute highly contagious viral disease characterized by sudden onset, fever, prostration, and progressive intimation of the respiratory mucous membrane.
The compounds of the present invention contain dioxobutanoic acids substituted with piperidine and similar N-substituted saturated cycloalkyls. Applicants demonstrate that the compounds of this invention are inhibitors of the cap-dependent endonuclease of influenza virus. The compounds were shown to be selective for influenza transcription by testing in several related enzyme assays. The compounds were not inhibitory in other polymerase assays including VSV transcription, HIV reverse transcriptase, T7 phage, Hela cell RNA polymerase II and Hela cell DNA polymerase .alpha. when tested at concentrations 100-500 fold above the IC.sub.50 for influenza transcription; thereby showing specific inhibition of influenza transcription. The inhibitory activity was specific to cap-dependent influenza transcription and had no effect upon influenza transcription primed cap-independently with the dinucleotide ApG. The mode of action of the inhibitors was demonstrated to be inhibition of cap-dependent endonuclease activity in an influenza cleavage assay in which the dioxobutanoic acids had IC.sub.50 s similar to those obtained in influenza transcription. Additionally, the inhibitor had no effect upon transcription when primed with capped substrates which did not undergo endonucleolytic processing, further confining inhibition of the influenza endonuclease. The specificity of influenza cleavage inhibition was demonstrated in nuclease counterscreens in which the compound had no effect upon RNases A, T1, U1 and HIV RNase H when tested up to 100-fold above the IC.sub.50 obtained in influenza cleavage.